Predicting Severe Immune-Related Toxicities in Lung Cancer Immunotherapy

In an interview with CancerNetwork® at the Big Ten Cancer Research Consortium (Big Ten CRC) Summit, Dwight H. Owen, MBBCh, MS, a medical oncologist at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), discussed how close clinicians are to identifying, before treatment begins, which patients are at highest risk for severe immune-related adverse events (irAEs).

Owen explained that no single test can yet predict which patients will develop serious toxicities from immune checkpoint inhibitors. He noted that a history of autoimmune disease is a known risk factor, but patients with no identifiable risk factors can still develop devastating, irreversible, or rarely fatal irAEs. He also described a central challenge: the patients who develop irAEs are often the ones most likely to benefit from immunotherapy.

As immunotherapies are increasingly combined with antibody-drug conjugates and oral targeted agents, Owen cautioned that overlapping toxicities, such as pneumonitis and neurologic events, may compound one another. He emphasized the importance of developing prediction models for monotherapies before combinations become standard. He expressed hope that larger datasets will eventually allow clinicians to risk-stratify patients and steer those at highest risk toward alternative treatments up front.

Transcript:

Unfortunately, today we still do not have a single test or technique that can predict this. However, it is a huge area of interest for the community broadly, and for me personally and our team at Ohio State. We know some patients are at higher risk of toxicity if they are receiving combination immunotherapies, such as patients with any history of autoimmune disorders. But patients may have no identifiable risk factor and still develop, in some cases, devastating, irreversible, and rarely even fatal toxicities from these treatments. If you had known that at the beginning, would you have changed your treatment recommendation? Generally, of course.

The hard part is that immunotherapy requires an immune system to work well, so the patients who develop immune-related toxicities are also the ones who are more likely to have benefited from treatment. There are also biases at play: a longer time on treatment tends to mean the treatment is working for the cancer, but it also exposes the patient to more risk of AEs.

As we combine more treatments, including immunotherapies, antibody-drug conjugates, and oral therapies, they have overlapping toxicities, and they may synergize in a negative way to increase the risk of severe AEs, including pneumonitis and some neurologic toxicities. It is important that we continue to develop prediction models for immune-related toxicities with monotherapies before we start combining these agents. As datasets grow and we better understand the necessary data inputs, I hope we will at least be able to risk-stratify which patients are more likely to develop serious, clinically significant, and potentially devastating toxicities, so that we can nudge them toward a different treatment up front.